Over 30 million people currently suffer from AMD, the most common cause of permanent vision loss among older adults. There are currently no approved therapies for geographic atrophy, which affects 90% of AMD patients (Meleth et al., 2011), or for juvenile-onset macular degenerations like Stargardt disease, which has a prevalence of 1 in 8000 children (Haji Abdollahi and Hirose, 2013).
This lack of effective treatments is largely due to limited insight into disease mechanisms. Current clinical trials for AMD and Stargardt disease are focused on stem cell transplants or intravitreal injections of antibodies to complement pathway proteins (clinicaltrials.gov), all of which require periodic (monthly to quarterly) injections into the vitreous. This mode of administration has been widely used to administer VEGF antibodies to treat wet AMD. Intravitreal injections have numerous unacceptable consequences including endophthalmitis, retinal detachment and increased risk of developing geographic atrophy (Lois, et al., 2013).
“Wet” AMD, also known as choroidal neovascularization, is caused by abnormal growth of choroidal blood vessels into the retina. Antibodies to vascular endothelial growth factor (VEGF) are currently used to prevent blood vessel growth. The more chronic form of the disease is called “dry” AMD, or geographic atrophy, where progressive degeneration of the retinal pigment epithelium and subsequent loss of overlying photoreceptors leads to a slow decline in central, high-resolution vision. There are no approved therapies for dry AMD.
A large-scale multicenter trial on high dose antioxidant and carotenoid supplements recently showed that the supplements slow the progression of AMD from early to late stages but do not prevent disease onset. EMIXUSTAT, a visual cycle modulator that decreases the formation of A2E and lipofuscin is currently in Phase II trials. In Phase I trials, EMIXUSTAT caused a dose-dependent delay in dark adaptation and dyschromatopsia (Kubota et al., 2012), suggesting that this could potentially limit its use in chronic diseases like dry AMD.
Thus, there is a strong need for small molecule lipophilic drugs with good safety profiles that can be administered orally or as topical formulations to the eye to treat macular dystrophies. Unlike hydrophilic drugs, lipophilic drugs can reach the retina by easily crossing the outer blood-retinal barrier, which is formed by the tight junctions of the retinal pigment epithelium (RPE).